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1.
Clin Epigenetics ; 13(1): 64, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33766110

RESUMO

BACKGROUND: Previous studies have shown that DNA methylation (DNAm) is associated with body mass index (BMI). However, it is unknown whether DNAm at pre-adolescence is associated with BMI status transition from pre- to post-adolescence. In the Isle of Wight (IoW) birth cohort, genome-wide DNA methylation in whole blood was measured using Illumina Infinium Human450 and EPIC BeadChip arrays in n = 325 subjects, and pre- to post-adolescence BMI transition was classified into four groups: (1) normal to normal, (2) normal to overweight or obese, (3) overweight or obese to normal, and (4) persistent overweight or obese. We used recursive random forest to screen genome-wide Cytosine-phosphate-Guanine (CpG) sites with DNAm potentially associated with BMI transition for each gender, and the association of BMI status transition with DNAm at an earlier age was assessed via logistic regressions. To evaluate gender specificity, interactions between DNAm and gender were included in the model. Findings in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). RESULTS: In total, 174 candidate CpGs were selected including CpGs from screening and CpGs previously associated correctionally with BMI in children and adults. Of these 174 CpGs, pre-adolescent DNAm of 38 CpGs in the IoW cohort was associated with BMI status transition, including 30 CpGs showing gender-specific associations. Thirteen CpGs showed consistent associations between the IoW cohort and the ALSPAC cohort (11 of which were gender-specific). CONCLUSION: Pre-adolescence DNAm is associated with the change in BMI status from pre- to post-adolescence and such associations are likely to be gender-specific.

2.
Psychol Med ; : 1-9, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33682658

RESUMO

BACKGROUND: The occurrence of early childhood adversity is strongly linked to later self-harm, but there is poor understanding of how this distal risk factor might influence later behaviours. One possible mechanism is through an earlier onset of puberty in children exposed to adversity, since early puberty is associated with an increased risk of adolescent self-harm. We investigated whether early pubertal timing mediates the association between childhood adversity and later self-harm. METHODS: Participants were 6698 young people from a UK population-based birth cohort (ALSPAC). We measured exposure to nine types of adversity from 0 to 9 years old, and self-harm when participants were aged 16 and 21 years. Pubertal timing measures were age at peak height velocity (aPHV - males and females) and age at menarche (AAM). We used generalised structural equation modelling for analyses. RESULTS: For every additional type of adversity; participants had an average 12-14% increased risk of self-harm by 16. Relative risk (RR) estimates were stronger for direct effects when outcomes were self-harm with suicidal intent. There was no evidence that earlier pubertal timing mediated the association between adversity and self-harm [indirect effect RR 1.00, 95% confidence interval (CI) 1.00-1.00 for aPHV and RR 1.00, 95% CI 1.00-1.01 for AAM]. CONCLUSIONS: A cumulative measure of exposure to multiple types of adversity does not confer an increased risk of self-harm via early pubertal timing, however both childhood adversity and early puberty are risk factors for later self-harm. Research identifying mechanisms underlying the link between childhood adversity and later self-harm is needed to inform interventions.

3.
Int J Epidemiol ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33729499

RESUMO

BACKGROUND: It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development. METHODS: We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer. RESULTS: The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer. CONCLUSIONS: DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.

4.
BMC Med ; 19(1): 33, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33612114

RESUMO

BACKGROUND: Mounting evidence suggests that maternal diet influences pregnancy and birth outcomes, but its contribution to the global epidemic of childhood obesity has not as yet been definitively characterized. We investigated whether maternal whole diet quality and inflammatory potential influence childhood adiposity. METHODS: We harmonized and pooled individual participant data from 16,295 mother-child pairs in seven European birth cohorts. Maternal pre-, early-, late-, and whole-pregnancy (any time during pregnancy) dietary quality and inflammatory potential assessed with the Dietary Approaches to Stop Hypertension (DASH) score and the energy-adjusted Dietary Inflammatory Index (E-DII™) score, respectively. Primary outcome was childhood overweight and obesity (OWOB) (age-and-sex-specific BMI z-score > 85th percentile). Secondary outcomes were sum of skinfold thickness (SST), fat mass index (FMI) and fat-free mass index (FFMI). We used multivariable regression analyses (adjusting for maternal lifestyle and sociodemographic factors) to assess the associations of maternal DASH and E-DII scores with offspring adiposity outcomes in cohort-specific analyses, with subsequent random-effect meta-analyses. RESULTS: The study mothers had a mean (SD) age of 30.2 (4.6) years and a mean BMI of 23.4 (4.2) kg/m2. Higher early-pregnancy E-DII scores (more pro-inflammatory diet) tended to be associated with a higher odds of late-childhood [10.6 (1.2) years] OWOB [OR (95% CI) 1.09 (1.00, 1.19) per 1-SD E-DII score increase], whereas an inverse association was observed for late-pregnancy E-DII score and early-childhood [2.8 (0.3) years] OWOB [0.91 (0.83, 1.00)]. Higher maternal whole pregnancy DASH score (higher dietary quality) was associated with a lower odds of late-childhood OWOB [OR (95% CI) 0.92 (0.87, 0.98) per 1-SD DASH score increase]; associations were of similar magnitude for early and late-pregnancy [0.86 (0.72, 1.04) and 0.91 (0.85, 0.98), respectively]. These associations were robust in several sensitivity analyses and further adjustment for birth weight and childhood diet did not meaningfully alter the associations and conclusions. In two cohorts with available data, a higher whole pregnancy E-DII and lower DASH scores were associated with a lower late-childhood FFMI in males and a higher mid-childhood FMI in females (P interactions < 0.10). CONCLUSIONS: A pro-inflammatory, low-quality maternal antenatal diet may adversely influence offspring body composition and OWOB risk, especially during late-childhood. Promoting an overall healthy and anti-inflammatory maternal dietary pattern may contribute to the prevention of childhood obesity, a complex health issue requiring multifaceted strategy.

5.
Clin Epigenetics ; 13(1): 40, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622391

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones. RESULTS: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%). CONCLUSIONS: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.

6.
Hum Mol Genet ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33481009

RESUMO

Integrating findings from genome-wide association studies with molecular datasets can develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization (MR) to investigate whether brain-derived gene expression (n = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome (PBonferroni < 6.72 × 10-6), with multiple-trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified evidence of enrichment which may reflect putative causal relationships, such as an inverse relationship between genetic liability towards schizophrenia risk and cognitive ability in later life. Repeating these analyses in whole blood (n = 31 684), we replicated 58.2% of brain-derived effects (based on P < 0.05). Finally, we undertook phenome-wide evaluations at associated loci to investigate pleiotropic effects with 700 complex traits. This highlighted pleiotropic loci such as FURIN (initially implicated in schizophrenia risk (P = 1.05 × 10-7)) which had evidence of an effect on 28 other outcomes, as well as genes which may have a more specific role in disease pathogenesis (e.g. SLC12A5 which only provided evidence of an effect on depression (P = 7.13 × 10-10)). Our results support the utility of whole blood as a valuable proxy for informing initial target identification but also suggest that gene discovery in a tissue-specific manner may be more informative. Finally, non-pleiotropic loci highlighted by our study may be of use for therapeutic translational endeavours.

7.
Hum Mol Genet ; 30(1): 119-134, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33450751

RESUMO

DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases, DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for non-linear change and inter-individual variation in non-linear trajectories was somewhat less common (11 and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. In contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often non-linear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.

8.
Mol Psychiatry ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414500

RESUMO

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

9.
Dev Psychopathol ; : 1-10, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33494854

RESUMO

While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: nbirth = 804, nage 7 = 877) and trajectories of social communication deficits at age 8-17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high (n = 80) versus low (n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated.

10.
Clin Epigenetics ; 13(1): 5, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407823

RESUMO

BACKGROUND: The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood. METHODS: DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex. RESULTS: High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases. CONCLUSION: The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.

11.
PLoS Med ; 18(1): e1003491, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33476335

RESUMO

BACKGROUND: Adverse birth outcomes are major causes of morbidity and mortality during childhood and associate with a higher risk of noncommunicable diseases in adult life. Maternal periconception and antenatal nutrition, mostly focusing on single nutrients or foods, has been shown to influence infant birth outcomes. However, evidence on whole diet that considers complex nutrient and food interaction is rare and conflicting. We aim to elucidate the influence of whole-diet maternal dietary inflammatory potential and quality during periconceptional and antenatal periods on birth outcomes. METHODS AND FINDINGS: We harmonized and pooled individual participant data (IPD) from up to 24,861 mother-child pairs in 7 European mother-offspring cohorts [cohort name, country (recruitment dates): ALSPAC, UK (1 April 1991 to 31 December 1992); EDEN, France (27 January 2003 to 6 March 2006); Generation R, the Netherlands (1 April 2002 to 31 January 2006); Lifeways, Ireland (2 October 2001 to 4 April 2003); REPRO_PL, Poland (18 September 2007 to 16 December 2011); ROLO, Ireland (1 January 2007 to 1 January 2011); SWS, United Kingdom (6 April 1998 to 17 December 2002)]. Maternal diets were assessed preconceptionally (n = 2 cohorts) and antenatally (n = 7 cohorts). Maternal dietary inflammatory potential and quality were ranked using the energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) index, respectively. Primary outcomes were birth weight and gestational age at birth. Adverse birth outcomes, i.e., low birth weight (LBW), macrosomia, small-for-gestational-age (SGA), large-for-gestational-age (LGA), preterm and postterm births were defined according to standard clinical cutoffs. Associations of maternal E-DII and DASH scores with infant birth outcomes were assessed using cohort-specific multivariable regression analyses (adjusted for confounders including maternal education, ethnicity, prepregnancy body mass index (BMI), maternal height, parity, cigarettes smoking, and alcohol consumption), with subsequent random-effects meta-analyses. Overall, the study mothers had a mean ± SD age of 29.5 ± 4.9 y at delivery and a mean BMI of 23.3 ± 4.2 kg/m2. Higher pregnancy DASH score (higher dietary quality) was associated with higher birth weight [ß(95% CI) = 18.5(5.7, 31.3) g per 1-SD higher DASH score; P value = 0.005] and head circumference [0.03(0.01, 0.06) cm; P value = 0.004], longer birth length [0.05(0.01, 0.10) cm; P value = 0.010], and lower risk of delivering LBW [odds ratio (OR) (95% CI) = 0.89(0.82, 0.95); P value = 0.001] and SGA [0.87(0.82, 0.94); P value < 0.001] infants. Higher maternal prepregnancy E-DII score (more pro-inflammatory diet) was associated with lower birth weight [ß(95% CI) = -18.7(-34.8, -2.6) g per 1-SD higher E-DII score; P value = 0.023] and shorter birth length [-0.07(-0.14, -0.01) cm; P value = 0.031], whereas higher pregnancy E-DII score was associated with a shorter birth length [-0.06(-0.10, -0.01) cm; P value = 0.026] and higher risk of SGA [OR(95% CI) = 1.18(1.11, 1.26); P value < 0.001]. In male, but not female, infants higher maternal prepregnancy E-DII was associated with lower birth weight and head circumference, shorter birth length, and higher risk of SGA (P-for-sex-interaction = 0.029, 0.059, 0.104, and 0.075, respectively). No consistent associations were observed for maternal E-DII and DASH scores with gestational age, preterm and postterm birth, or macrosomia and LGA. Limitations of this study were that self-reported dietary data might have increased nondifferential measurement error and that causality cannot be claimed definitely with observational design. CONCLUSIONS: In this cohort study, we observed that maternal diet that is of low quality and high inflammatory potential is associated with lower offspring birth size and higher risk of offspring being born SGA in this multicenter meta-analysis using harmonized IPD. Improving overall maternal dietary pattern based on predefined criteria may optimize fetal growth and avert substantial healthcare burden associated with adverse birth outcomes.

12.
Sci Rep ; 11(1): 2329, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504897

RESUMO

Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.

13.
Biol Psychiatry ; 89(6): 550-559, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33358009

RESUMO

BACKGROUND: The impact of maternal diet during pregnancy on child neurodevelopment is of public health and clinical relevance. We evaluated the associations of dietary quality based on the Dietary Approaches to Stop Hypertension (DASH) score and dietary inflammatory potential based on the energy-adjusted Dietary Inflammatory Index (E-DII) score during pregnancy with emotional and behavioral symptoms of offspring at 7 to 10 years of age. METHODS: Individual participant data for 11,870 mother-child pairs from four European cohorts participating in the ALPHABET project were analyzed. Maternal antenatal DASH and E-DII scores were generated from self-completed food frequency questionnaires. Symptoms of depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder in children were assessed using mother-reported tests and classified within the normal or borderline/clinical ranges using validated cutoffs. Adjusted odds ratios were determined by multivariable logistic regression models and aggregated by the two-level individual participant data meta-analysis method. RESULTS: Higher maternal DASH scores (indicating better dietary quality) were associated with lower risk of depressive and anxiety symptoms, aggressive behavior symptoms, and attention-deficit/hyperactivity disorder symptoms within the borderline/clinical ranges: odds ratio [OR] 0.97, 95% confidence interval [CI], 0.95-0.99; OR 0.97, 95% CI, 0.94-0.99; OR 0.97, 95% CI, 0.95-0.98, per one-unit DASH score increase, respectively. For depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder symptoms, a one-unit increase in E-DII scores (a more proinflammatory diet) was associated with a 7% increased risk of all three analyzed emotional and behavioral symptoms: OR 1.07, 95% CI, 1.03-1.11; OR 1.07, 95% CI, 1.02-1.13; OR 1.07, 95% CI, 1.01-1.13, respectively. CONCLUSIONS: Our findings suggest that a maternal low-quality and proinflammatory diet may increase the risk of emotional and behavioral symptoms in children.

14.
ERJ Open Res ; 6(4)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33263047

RESUMO

Background: Age of pubertal onset is associated with height and lung function in adulthood. It is unknown whether height growth in adolescence mediates the association of age at puberty with early adult lung function. Methods: Data from the Isle of Wight (IOW) birth cohort (n=1261) were examined in the study. Ages of pubertal events, height at ages 10 and 18 years and lung function parameters (forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)) at 26 years were included in a path analysis to assess the mediation effects of height growth. Findings were tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Results: In females in the IOW cohort, age at menarche and body hair growth showed a positive indirect association with FVC (menarche: indirect effect coefficient (IEC)=0.13, 95% CI 0.05-0.20, p=1.28×10-3; body hair growth: IEC=0.08, 95% CI 0.01-0.15, p=0.017) and FEV1 (menarche: IEC=0.09, 95% CI 0.01-0.17, p=0.028; body hair growth: IEC=0.07, 95% CI 0.01-0.14, p=0.043) at 26 years through height growth and lung function at 18 years. In males, age at body hair growth (IEC=0.08; 95% CI 0.01-0.15, p=0.047), growth spurt (IEC=0.09; 95% CI 0.01-0.17, p=0.034) and facial hair growth (IEC=0.09; 95% CI 0.02-0.16, p=0.014) had positive indirect effects on FVC at 26 years, but voice deepening did not show statistically significant indirect effects (p>0.05). For pubertal events available in the ALSPAC cohort, results consistent with the IOW cohort were found for both females and males. Conclusion: Effects of age of puberty on FVC in early adulthood are likely mediated by height growth during adolescence.

15.
Int J Epidemiol ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33306803

RESUMO

BACKGROUND: Despite a clear association seen in congenitally infected children, the effect of postnatal cytomegalovirus (CMV) infection during early childhood on cognitive development has not yet been determined. METHODS: CMV-infection status was obtained based on serological measurements when children were 7 years old. Using population-based longitudinal data, we employed multivariate Poisson regression with a robust variance estimator to characterize the relationship between childhood CMV infection and adverse neurocognitive outcomes in children. Suboptimal neurocognitive outcomes were compared between CMV-positive and CMV-negative children using various cognitive assessments from 8 to 15 years of age. Children were evaluated on the cognitive domains of language, reading, memory and general intelligence, with a suboptimal score being >2 standard deviations lower than the mean score. Approximate Bayes factor (ABF) analysis was used to determine the level of evidence for the observed associations. RESULTS: With adjustment for potential confounders, we observed that early-childhood CMV infection was associated with suboptimal total intelligence quotient (IQ) at 8 years of age [incidence-rate ratio (IRR) = 2.50, 95% confidence interval (CI) 1.35-4.62, ABF = 0.08], but not with suboptimal total IQ at 15 years of age (IRR = 0.97, 95% CI 0.43-2.19, ABF = 1.68). Suboptimal attentional control at 8 years (IRR = 1.74, 95% CI 1.13-2.68, ABF = 0.18) and reading comprehension at 9 years (IRR = 1.93, 95% CI 1.12-3.33, ABF = 0.24) were also associated with CMV infection. ABF analysis provided strong evidence for the association between CMV infection and total IQ at 8 years, and only anecdotal evidence for attentional control at 8 years and reading comprehension at 9 years. All other cognitive measures assessed were not associated with CMV infection. CONCLUSION: In this large-scale prospective cohort, we observed some evidence for adverse neurocognitive effects of postnatal CMV infection on general intelligence during early childhood, although not with lasting effect. If confirmed, these results could support the implementation of preventative measures to combat postnatal CMV infection.

16.
BMC Med ; 18(1): 366, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33222689

RESUMO

BACKGROUND: Prediction of pregnancy-related disorders is usually done based on established and easily measured risk factors. Recent advances in metabolomics may provide earlier and more accurate prediction of women at risk of pregnancy-related disorders. METHODS: We used data collected from women in the Born in Bradford (BiB; n = 8212) and UK Pregnancies Better Eating and Activity Trial (UPBEAT; n = 859) studies to create and validate prediction models for pregnancy-related disorders. These were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), small for gestational age (SGA), large for gestational age (LGA) and preterm birth (PTB). We used ten-fold cross-validation and penalised regression to create prediction models. We compared the predictive performance of (1) risk factors (maternal age, pregnancy smoking, body mass index (BMI), ethnicity and parity) to (2) nuclear magnetic resonance-derived metabolites (N = 156 quantified metabolites, collected at 24-28 weeks gestation) and (3) combined risk factors and metabolites. The multi-ethnic BiB cohort was used for training and testing the models, with independent validation conducted in UPBEAT, a multi-ethnic study of obese pregnant women. RESULTS: Maternal age, pregnancy smoking, BMI, ethnicity and parity were retained in the combined risk factor and metabolite models for all outcomes apart from PTB, which did not include maternal age. In addition, 147, 33, 96, 51 and 14 of the 156 metabolite traits were retained in the combined risk factor and metabolite model for GDM, HDP, SGA, LGA and PTB, respectively. These include cholesterol and triglycerides in very low-density lipoproteins (VLDL) in the models predicting GDM, HDP, SGA and LGA, and monounsaturated fatty acids (MUFA), ratios of MUFA to omega 3 fatty acids and total fatty acids, and a ratio of apolipoprotein B to apolipoprotein A-1 (APOA:APOB1) were retained predictors for GDM and LGA. In BiB, discrimination for GDM, HDP, LGA and SGA was improved in the combined risk factors and metabolites models. Risk factor area under the curve (AUC 95% confidence interval (CI)): GDM (0.69 (0.64, 0.73)), HDP (0.74 (0.70, 0.78)) and LGA (0.71 (0.66, 0.75)), and SGA (0.59 (0.56, 0.63)). Combined risk factor and metabolite models AUC 95% (CI): GDM (0.78 (0.74, 0.81)), HDP (0.76 (0.73, 0.79)) and LGA (0.75 (0.70, 0.79)), and SGA (0.66 (0.63, 0.70)). For GDM, HDP and LGA, but not SGA, calibration was good for a combined risk factor and metabolite model. Prediction of PTB was poor for all models. Independent validation in UPBEAT at 24-28 weeks and 15-18 weeks gestation confirmed similar patterns of results, but AUCs were attenuated. CONCLUSIONS: Our results suggest a combined risk factor and metabolite model improves prediction of GDM, HDP and LGA, and SGA, when compared to risk factors alone. They also highlight the difficulty of predicting PTB, with all models performing poorly.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33187967

RESUMO

BACKGROUND: Past history of gallstones is associated with increased risk of gallbladder cancer (GBC) in observational studies. We conducted complementary observational and Mendelian Randomization (MR) analyses to determine whether history of gallstones is causally related to development of GBC in an Indian population. METHODS: To investigate associations between history of gallstones and GBC, we used questionnaire and imaging data from a GBC case-control study conducted at Tata Memorial Hospital, Mumbai (cases=1170; controls=2525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstones cases and 736,838 controls of European ancestry in a Mendelian randomization approach to assess causality. The association of these genetic variants with both gallstones and GBC was examined in the GBC case-control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population. RESULTS: We found a strong observational association between gallstones and GBC using self-reported history of gallstones (OR=4.5, 95%CI=3.5-5.8) and with objective measures of gallstone presence using imaging techniques (OR=2.0, 95%CI=1.5-2.7). We found consistent causal estimates across all MR techniques, with odds ratios for GBC in the range of 1.3-1.6. CONCLUSIONS: Our findings indicate a causal relationship between history of gallstones and increased risk of GBC, albeit of a smaller magnitude to those found in observational analysis. IMPACT: Our findings emphasise the importance of gallstone treatment for preventing GBC in high risk individuals.

18.
Transl Psychiatry ; 10(1): 398, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184255

RESUMO

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

19.
Clin Exp Allergy ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33150670

RESUMO

BACKGROUND: Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma. OBJECTIVE: We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific. METHODS: Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed. RESULTS: We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P-values <1.0 × 10-3 ). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (P-values <.01 in both cohorts). CONCLUSION AND CLINICAL RELEVANCE: Gender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.

20.
Eur Respir J ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214203

RESUMO

Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBC-F2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

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